Focus on Rare genetic variants in bipolar disorder: how outliers help understand complex disorders

Abstract

There is a long-standing debate between those who support the Common Disease Common Variant (CDCV) approach to the study of disorders with complex inheritance and those who argue in favour of a search for rare variants [Common Disease Rare Variant (CDRV); Doris, 2002]. The CDCV approach is based on the well-accepted assumption that for most complex disorders, including schizophrenia and bipolar disorder, inheritance is multifactorial with several genetic variants interacting with each other and with the environment to cause the disease. Because these disorders are relatively common, it is assumed that causative variants should be common too. The high prevalence of these variants and the fact that each one of them is neither sufficient nor obligatory by itself to cause the disease makes them difficult to identify. Indeed, until today not one common genetic variant has been shown to be associated with psychiatric disease beyond doubt, at least to the same extent that ApoE4 is associated with Alzheimer's disease. Supporters of the CDRV approach are not necessarily opposed to the idea that most cases of complex disorders are caused by common genetic variants. Rather, they suggest a ‘shortcut’ to the identification of the involved genes by the use of special outlier cases - extreme phenotypes, patients with chromosomal aberrations, or the study of large multiplex pedigrees. In all of these instances the hope is that inheritance is more Mendelian in nature, with a variant of major effect contributing to a large extent to the aetiology of the disorder.